The pharmacologically active phenothiazines have been shown to inhibit the neuro-homonally-induced accumulation of cyclic AMP in several preparations from rat and rabbit brain. Recent observations in this laboratory have revealed that in in vitro tissue slice preparations the phenothiazines act to elevate the accumulation of the other naturally occurring cyclic nucleotide, cyclic GMP. Therefore, the goal of this research proposal is to evaluate the role of the phenothiazines and tricyclic anti-depressants with regard to actions on central guanylate cyclase-cyclic GMP systems. A variety of approaches will be utilized to perform these investigations, namely, influence of these drugs in vitro-tissue slices, influence in isolated neuronal and glial guaylate cyclase preparations and influence in vivo on levels of cyclic AMP and cyclic GMP in rapidly fixed-microwave irradiated areas of mouse and rat brain. Dr. Nelson Goldberg postulated that cyclic AMP and GMP may mediate opposing actions and the preliminary data with the actions of phenothiazines on the two cyclic nucleotides in vitro support this theory. Hopefully these investigations will lead to a better understanding of the molecular actions of phenothiazines and tricyclic antidepressants.